TRAF6 is an amplified oncogene bridging the RAS and NF-κB pathways in human lung cancer.

Abstract

Somatic mutations and copy number alterations (as a result of deletion or amplification of large portions of a chromosome) are major drivers of human lung cancers. Detailed analysis of lung cancer-associated chromosomal amplifications could identify novel oncogenes. By performing an integrative cytogenetic and gene expression analysis of non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC) cell lines and tumors, we report here the identification of a frequently recurring amplification at chromosome 11 band p13. Within this region, only TNF receptor-associated factor 6 (TRAF6) exhibited concomitant mRNA overexpression and gene amplification in lung cancers. Inhibition of TRAF6 in human lung cancer cell lines suppressed NF-κB activation, anchorage-independent growth, and tumor formation. In these lung cancer cell lines, RAS required TRAF6 for its oncogenic capabilities. Furthermore, TRAF6 overexpression in NIH3T3 cells resulted in NF-κB activation, anchorage-independent growth, and tumor formation. Our findings show that TRAF6 is an oncogene that is important for RAS-mediated oncogenesis and provide a mechanistic explanation for the previously apparent importance of constitutive NF-κB activation in RAS-driven lung cancers.

• Authors: Daniel T Starczynowski, William W Lockwood, Sophie Deléhouzée, Raj Chari, Joanna Wegrzyn, Megan Fuller, Ming-Sound Tsao, Stephen Lam, Adi F Gazdar, Wan L Lam, Aly Karsan
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 121 Issue 10 Pg. 4095-105 (Oct 2011) ISSN: 1558-8238 [Electronic] United States
• PMID: 21911935 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• NF-kappa B
• TNF Receptor-Associated Factor 6
• ras Proteins

Topics

• Animals
• Carcinoma, Non-Small-Cell Lung (etiology, genetics, metabolism)
• Carcinoma, Small Cell (etiology, genetics, metabolism)
• Cell Line, Tumor
• Cell Transformation, Neoplastic (genetics)
• Chromosomes, Human, Pair 11 (genetics)
• Gene Amplification
• Humans
• Lung Neoplasms (etiology, genetics, metabolism)
• Mice
• Mice, Inbred NOD
• Mice, SCID
• NF-kappa B (metabolism)
• NIH 3T3 Cells
• Oncogenes
• Signal Transduction
• TNF Receptor-Associated Factor 6 (deficiency, genetics)
• Tumor Stem Cell Assay
• ras Proteins (metabolism)